The addictive nature of nicotine remains a global health problem and smoking-related illness is the largest preventable cause of death. Despite the availability of treatments for smoking cessation, relapse to smoking after quit attempts still remains very high. Neural circuits of addiction extensively overlap with those that support cognitive functions. Therefore, delineation of cognitive mechanisms that determine relapse during nicotine withdrawal is likely to provide gainful insights into the neurobiology of nicotine addiction. The frontostriatal circuits subserve executive functions including cognitive control and decision-making processes, and disruption in these circuits may contribute to compulsive drug use and loss of control in addiction. Although the effects of nicotine withdrawal on motivational states and hippocampus-dependent learning are well studied, how it affects frontostriatal circuits and top-down cognitive control is not known. This small grant (RO3) application seeks support for research focused on examining the effects of nicotine withdrawal on flexible decision-making. Because brain-derived neurotrophic factor (BDNF), a neurotrophic factor critical for synaptic plasticity, learning and conditioned reward is implicated in addiction, we will also determine whether cognitive changes following nicotine withdrawal are associated with alterations in corticostriatal BDNF signaling. The experiments of aim 1 will demonstrate that early (24 hr.) withdrawal from chronic nicotine will produce deficits in strategy set-shifting in mice performing an operant cognitive flexibility task due to impairments in execution of a new learning strategy. These deficits are predicted to be associated with epigenetic changes in the BDNF gene and increased BDNF expression in the corticostriatal circuits. Learning deficits and BDNF expression will be restored during the extended (30 d) withdrawal period. Experiments in Aim 2 will utilize Cre/loxP recombination to produce region-specific deletion of the BDNF gene in mice. These studies will determine whether BDNF knockdown in the prefrontal cortex and consequent reduction of BDNF protein levels in the striatum would restore early withdrawal-related deficits in strategy set-shifting. Collectively, the pilot data generated from this small gant will form the basis for future research to establish a causal link between chronic nicotine- and withdrawal-induced deficits in executive functions and corticostriatal BDNF signaling. This research would inform us about cognitive mechanisms underlying nicotine withdrawal that lead to higher relapse rate among smokers and the potential of targeting BDNF signaling for smoking cessation.